rs2125443

Variant names:

• chr5-146849865-G-A
• rs2125443
• NM_181675.4:c.70+28137C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-146849865-G-A
• chr5-146849865-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181675.4(PPP2R2B):​c.70+28137C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 151,956 control chromosomes in the GnomAD database, including 2,842 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2842 hom., cov: 32)
• Consequence: PPP2R2B NM_181675.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.764
• Publications: 7 publications found

Genes affected

PPP2R2B (HGNC:9305): (protein phosphatase 2 regulatory subunit Bbeta) The product of this gene belongs to the phosphatase 2 regulatory subunit B family. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a beta isoform of the regulatory subunit B55 subfamily. Defects in this gene cause autosomal dominant spinocerebellar ataxia 12 (SCA12), a disease caused by degeneration of the cerebellum, sometimes involving the brainstem and spinal cord, and in resulting in poor coordination of speech and body movements. Multiple alternatively spliced variants, which encode different isoforms, have been identified for this gene. The 5' UTR of some of these variants includes a CAG trinucleotide repeat sequence (7-28 copies) that can be expanded to 55-78 copies in cases of SCA12. [provided by RefSeq, Jul 2016]

PPP2R2B Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	NM_181675.4	MANE Select	c.70+28137C>T		intron	N/A	NP_858061.3
	PPP2R2B	NM_181674.3		c.268+28137C>T		intron	N/A	NP_858060.2
	PPP2R2B	NM_001271900.2		c.244+28137C>T		intron	N/A	NP_001258829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R2B	ENST00000394411.9	TSL:2 MANE Select	c.70+28137C>T		intron	N/A	ENSP00000377933.3
	PPP2R2B	ENST00000394414.5	TSL:1	c.268+28137C>T		intron	N/A	ENSP00000377936.1
	PPP2R2B	ENST00000394409.7	TSL:1	c.70+28137C>T		intron	N/A	ENSP00000377931.4

Frequencies

GnomAD3 genomes AF: 0.191 AC: 28954 AN: 151838 Hom.: 2846 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.194

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.191 AC: 28967 AN: 151956 Hom.: 2842 Cov.: 32 AF XY: 0.188 AC XY: 13984 AN XY: 74266

African (AFR) AF: 0.188 AC: 7774 AN: 41402

American (AMR) AF: 0.184 AC: 2809 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 605 AN: 3464

East Asian (EAS) AF: 0.351 AC: 1812 AN: 5156

South Asian (SAS) AF: 0.217 AC: 1045 AN: 4824

European-Finnish (FIN) AF: 0.131 AC: 1380 AN: 10546

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12930 AN: 67986

Other (OTH) AF: 0.190 AC: 401 AN: 2106

Alfa AF: 0.186 Hom.: 4790

Bravo AF: 0.197

Asia WGS AF: 0.260 AC: 903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.57
DANN	Benign	0.46
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2125443; hg19: chr5-146229428; COSMIC: COSV60758825;